EDITORIALS

Personalization and Pragmatism: Pediatric

Intracranial Pressure and Cerebral Perfusion
Pressure Treatment Thresholds*
J. N. Stroh, PhD1
KEY WORDS: cerebral perfusion pressure; intracranial pressure;
David J. Albers, PhD1,2
pediatrics; physiologic monitoring; traumatic brain injury
Tellen D. Bennett, MD, MS2,3

N
eurocritical care after brain injury is designed to prevent secondary
injury and create optimal conditions for survival of recoverable brain
tissue. The most important component of this approach is to limit
global or regional cerebral ischemia. To accomplish that, we attempt to avoid
excessive elevation of intracranial pressure (ICP) and maintain adequate cere-
bral perfusion pressure (CPP). However, the ideal ICP and CPP targets for a
given patient are not known (1).
The ICP treatment threshold of 20 mm Hg recommended by pediatric trau-
matic brain injury (TBI) treatment guidelines (2) has not changed in 2 decades
(Table 1), despite relatively weak supporting evidence. Recommended pedi-
atric CPP thresholds have decreased and become less age-dependent despite
known age-related changes in mean arterial pressure (MAP), cerebral blood
flow (CBF), and cerebral metabolic rate of oxygen.
Simultaneously, the field is undergoing a vigorous debate about whether
fixed ICP or CPP treatment thresholds should exist (3, 4). Heterogeneity is a
signature of TBI and other forms of brain injury, relationships between CBF,
CPP, cerebral oxygen delivery and utilization, and cellular metabolism are com-
plex, and ICP time series have many features other than whether or not a treat-
ment threshold is crossed (3). Personalized therapy has become the standard in
oncology and other medical specialties. Multimodal invasive monitoring can
inform one form of personalized therapy guided by cerebrovascular pressure re-
activity, brain tissue oxygenation, cerebral metabolism, and electrophysiology.
However, it is invasive, resource-intensive, and not often used in children.
Others have argued for a pragmatic form of ICP-guided therapy designed
to limit treatment toxicity: noninvasive ICP monitoring first, less invasive ICP
monitoring overall, and more generalized ICP and CPP targets (4). The distinc-
tion between a threshold that should not be breached and a threshold where
treatment should begin (indicating some wiggle room) is important. A land-
mark trial in adults with TBI found no difference in outcome between intensive
imaging- and clinical examination-guided therapy compared with ICP-guided
therapy (5). *See also p. 135.
Against this backdrop, Woods et al (6) report the results of a retrospective Copyright © 2021 by the Society of
cohort study in this issue of Pediatric Critical Care Medicine. The cohort was Critical Care Medicine and the World
262 children who received an ICP monitor for any indication at a single center Federation of Pediatric Intensive and
during 2012–2016. The study aimed to evaluate for associations between each Critical Care Societies
child’s mean hourly ICP and CPP values and subsequent in-hospital mortality. DOI: 10.1097/PCC.0000000000002637

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Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
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 Editorials
TABLE 1.
Guideline-Recommended Intracranial Pressure and Cerebral Perfusion Pressure Treatment
Thresholds
Year 2000 2003
Treatment threshold
Intracranial pressure
  Adult 20–25
  Pediatric 20
Cerebral perfusion pressure
  Adult 70
  Pediatric 40
   “Age-related continuum” 40–65
Intracranial pressure and cerebral perfusion pressure treatment thresholds, in mm Hg, recommended by each edition of the Severe Trau-
matic Brain Injury Treatment Guidelines for adults and children.
They developed ICP and CPP thresholds to test by gen-
erating cut-points based on Youden index. The authors
conducted subgroup analyses for children with (n = 87)
and without (n = 175) TBI and across three prespeci-
fied age groups (< 2 yr old, 2–8 yr old, and ≥ 8 yr old).
The authors found that a mean ICP greater than
15 mm Hg (non-TBI) and greater than 18 mm Hg
(TBI) was associated with mortality. These threshold
values are lower than current guideline recommen-
dations (Table 1) and agree with other pediatric
studies (7). They also agree with a recent analysis of
ICP-monitored adults (8) that found that ICP values
greater than 19 mm Hg (lower than the currently rec-
ommended adult threshold [Table 1]) were associated
with mortality.
In addition, children with TBI with mean CPP less
than 67 mm Hg (much higher than in current guide-
lines) had higher mortality. No such association was
found in the non-TBI group. This is a valuable con-
tribution. ICP and CPP thresholds developed for
children with TBI are frequently applied to children
without TBI, but few studies to date have explicitly
addressed whether this is appropriate or not. The need
for comparative studies is particularly acute as the TBI
guidelines become more evidence-based over time.
In the combined cohort, the CPP thresholds as-
sociated with mortality increased with patient age:
47, 58, and 73 in the three age groups. This analysis
is a significant strength of the article. Whether or not
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2007 2012 2017 2019
20 22
20 20
50–70 60–70
40 40
40–50 40–50
ICP and CPP thresholds should be age-dependent is a
critical knowledge gap in the current pediatric guide-
lines. Sound physiologic arguments for age-dependent
thresholds exist, but the field has lacked clinical evi-
dence of sufficient strength to inform practice. The
study by Woods et al (6) in isolation is not enough, but
it should inform additional work to answer this impor-
tant question.
One obstacle to advancing our understanding is
the lack of a known normal value for ICP in children.
Neither the definition of pediatric intracranial hy-
pertension nor therapeutic guidelines have a useful
baseline ICP reference. A recent study in adults (8)
identified 8 and 9 mm Hg as the most common ICP
values in ICP-monitored adults. No pediatric equiva-
lent is known. It is certainly plausible that normal ICP
values would change with cerebrovascular develop-
ment and be age-dependent.
Another strength of this article is the attempt to lev-
erage dense clinically collected data to inform clinical
practice. As in this article, hourly vital signs in elec-
tronic health records are typically bedside monitoring
system outputs selected and validated by nurses. These
hourly values are already “smoothed”—nurses have
typically removed outliers and selected a value repre-
sentative of the signal during that hour. More granular
“unvalidated” signals from continuous monitors are a
relatively untapped resource for building clinical deci-
sion support (CDS) systems.
February 2021 • Volume 22 • Number 2

The article also has several weaknesses. One problem
is that ICP and CPP values are nearly always collected
from children with brain injury who are receiving
threshold-guided therapies. Correspondingly, persist-
ently elevated ICP and/or depressed CPP may largely
reflect injury severity. We have long known that chil-
dren whose ICP we can lower have better outcomes
than those whose ICP we cannot (2). Second, in-hos-
pital mortality is a fairly insensitive outcome measure.
Assessment using validated outcome scales several
months after injury is now the gold standard. In a re-
lated issue, important confounders were not considered
in the mortality models. These include known predic-
tors of poor outcome after TBI such as penetrating in-
jury, nonaccidental trauma, severe nonhead injuries,
and cardiac arrest as well as lethal non-TBI conditions
such as hemophagocytic lymphohistiocytosis and suba-
rachnoid hemorrhage. The lack of confounding adjust-
ment was largely due to the relatively small single-center
sample size, which also limits the study’s generalizability.
Given the heterogeneous pathophysiology, separate TBI
and non-TBI mortality models would be more appro-
priate than a TBI covariate in a single model.
The idea that mean, minimum, and maximum ICP
and CPP values accurately represent the contribution
of ICP and CPP to mortality has several challenges.
Averaged data may fail to account for intermittent peri-
ods of threshold crossing associated with secondary
injury (9). Among those who ultimately die, max-
imum ICP may occur at the end of aggressive attempts
to support a patient and proximate to a decision to
limit or withdraw interventions. Among those who ul-
timately survive, maximum ICP may occur at a variety
of different times. Means are sensitive to outliers. Local
practice regarding how long ICP monitors are left in
could powerfully influence the observational data
available. The relative impact of transient elevations or
the amount of time spent with elevated ICP can only
be assessed using “pressure-time indices” (7, 10). Fixed
treatment thresholds could lead to harmful under- or
over-treatment. Finally, the pathway to translation for
models such as those presented in this article is in CDS
systems. Means, minima, and maxima are not viable
prospective predictors in CDS systems because they
are not available until all data have accumulated.
Another method to personalize treatment is to use
computational physiology models paired with data as-
similation methods, which optimize model state and
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Editorials
parameters to external observations (11). Personalized
model output could be used to customize treatment
on the basis of both estimated and observed ICP as
well as other observed patient data. Existing mod-
eling approaches (12, 13) and their extensions deserve
attention for potential roles in future TBI manage-
ment. In particular, such models can be conditioned
on monitored quantities such as ICP, MAP, and oxy-
genation to provide numerical estimates of autoregula-
tory function and adaptive capacity. Estimates of these
mechano-physiologic properties should better inform
appropriate treatment thresholds for TBI management.
In order to advance generalizable personalized
therapy, the field needs multicenter sharing and inte-
gration of ICP, MAP, and other signal data from a wide
variety of patients. Hourly nurse-validated signal data
likely do not have sufficient resolution to represent all
of the physiologic processes linked to patient outcome.
Analysis of ICP waveforms and other signal-derived
time series may be one method to target therapeutic
guidelines on the basis of empirical injury pheno-
types (14). The Brain-IT (http://www.brainit.org) and
PhysioNet (https://physionet.org) groups have made
progress in collecting and sharing such signals, but
more remains to be done. One open question is how
dense the signals need to be. Every 1-minute sam-
pling frequency may be sufficient for many studies (8).
Other studies may require highly granular signals that
allow beat-to-beat resolution (12, 13).
Pragmatic ICP and CPP treatment thresholds will
still be needed. The global burden of TBI still falls
heaviest on low- and middle-income countries (15)
where ICP monitoring is inconsistently available, let
alone multimodal monitoring and other sophisticated
care. Models developed using higher resolution signal
data paired with robust injury and patient descriptors
and studies of their application in prospective use will
inform a better balance of benefits and risks from ICP-
targeted therapies guided by both personalized and
pragmatic treatment thresholds.
1 Department of Bioengineering, College of Engineering,
Design, and Computing, Aurora, CO
2 Section of Informatics and Data Science, Department of
Pediatrics, University of Colorado School of Medicine,
Aurora, CO
3 Section of Critical Care Medicine, Department of Pediatrics,
University of Colorado School of Medicine, Aurora, CO
www.pccmjournal.org     215
 Editorials
Dr. Albers was supported by National Institutes of Health (NIH)/
National Library of Medicine 5R01LM012734 and Dr. Bennett
was supported by NIH/Eunice Kennedy Shriver National Institute
of Child Health and Human Development 5R03HD094912.
Dr. Stroh’s institution received funding from National Institutes
of Health (NIH)/National Library of Medicine and Eunice
Kennedy Shriver National Institute of Child Health and Human
Development (NICHD). Drs. Stroh, Albers, and Bennett received
support for article research from the NIH. Dr. Bennett’s institu-
tion received funding from NIH/NICHD and National Center for
Advancing Translational Sciences.
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